Chs ch



United States Patent MONO- AND BIS-(TERTIARY AMINOALKYL-AMINO)-p-BENZOQUINONES Chester J. Cavallito, Ravena, N. Y., assignor toSterling Drug Inc., New York, N. Y., a corporation of Delaware NoDrawing. Original application October 5, 1949, Serial No. 119,760.Divided and this application November 6, 1951, Serial No. 261,575

Claims. (Cl. 260-294.7)

This invention relates to a particular group of (tertiaryamino)alkylamino-p-benzoquinones and acid addition salts thereof, and toprocesses for their production.

In addition to being useful as intermediates for the preparation ofhighly active curarirnimetic agents by conversion to quaternary ammoniumcompounds as described hereinafter, the novel (tertiaryamino)alkylamino-p-benzoquinones of my invention are valuable, per

se and in the form of their simple addition salts with acids, aspharmaceutical agents. In particular, these amines exhibit a moderatecurarimimetic activity which adapts them to use in special cases wherean agent of such activity is desired. The novel amines of my inventionhave the general formula where Q is a member of the group of (tertiaryamino)- :xlkylamino radicals having the formula hydrogen, (loweralkyl)amino, di-(lower alkyl)amino,

and (tertiary amino)alkylamino radicals having the formula NH--Y -N=B.By the term lower alky as applied to the definitions of --N=B and Z Imean to include alkyl radicals containing 1-5 carbon atoms. Examples ofthe members of this group of amlnes include:

(a) 2,5 bis (3 diethylaminopropylamino) p benzoquinone;

(b) 2 [3 (1 piperidy1)propylamino] p benzoquinone;

(c) 2 [3 (2 methyl 1 piperidyl)propylam1no] p-benzoquinone;

(d) 2 [3 (1 pyrrolidyl)propylamino] p benzoquinone;

(e) 2,5 bis [3 (1 piperidyl)propylamino] p benzoquinone;

(f) 2 (4 diethylaminobutylamino) p benzoquinone;

(g) 2 (4 diethylaminobutylamino) 5 methylamino p-benzoquinone;

(h) 2 (4 diethylaminobutylamino) 5 -dirnethylamino-p-benzoquinone;

(i) 2,5 bis -(4 diethylaminobutylamino) p benzoquinone;

(j) 2,5 bis (5 diethylaminoamylamino) p benzoquinone; and

(k) 2,5 bis [5 (1 piperidyl)amylam1no] p benzoquinone.

All of these bases form salts with organic and inorganic acids havingthe formula H-An, where An 1s a nontoxic anion. These salts, in WhlChform the amines are 2,701,247 Patented Feb. 1 1955 When Z is a (tertiaryamino)alkylamino group, the amines react with two equivalents of theacid. Among the more useful salts there can be mentioned those withhydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid,nitric acid, citric acid, etc.

My invention comprises: interacting a p-benzoquinone with one or twomolecular equivalents of a primary N-[(tertiary amino)alkyl]-amine underconditions of mild oxidation to yield, respectively, a 2-monoor a2,5-bis- N- (tertiary amino) allcylamino] -p-benzoquinone; and, ifdesired, converting the reaction product thus obtained to an acidaddition salt.

The new class of quaternary ammonium compounds disclosed and claimed inmy parent copending U. S. patent application Ser. No. 119,760, filedOctober 5, 1949, which includes compounds formed by quaternizing thenovel amines disclosed and claimed in the instant application, has thegeneral formula where Q is a member of the group ofiminoalkyl-(quaternary ammonium) radicals having the formula where Y isa lower alkylene bridge interposing 2-5 carbon atoms between the twonitrogen atoms connected by the bridge, N(tert) is a tertiary amineradical, R is hydrogen or methyl, and An is a non-toxic anion; Z is amemberof the group consisting of hydrogen, alkylamino radicals,dialkylamino radicals, and iminoalkyl- (quaternary ammonium) radicalshaving the formula and X and X are each hydrogen or, when Z is animinoalkyl-(quaternary ammonium) radical, X and X are each hydrogen or amiddle halogen, i. e. chlorine or bromine. The iminoalkyl-(quaternaryammonium) radicals Q and Z can be the same or different, as desired.Thus, all of my new quaternary compounds contain the parent structure orcan be considered as derived therefrom by introduction of the abovespecified substituents in one or more of the 3, 5, and 6 positions ofthe parent structure, such substituents including particularly a. secondiminoalkyl- (quaternary ammonium) radical in the 5-position.

Represented ionically, these quaternary ammonium compounds have thestructure I it The quaternary ammonium grouping, [N(tert)]+, makes itschief contribution to the physiological activity of my new compounds byvirtue of the electrostatic field set up at the site of the quaternarynitrogen. Since this contribution is inherent in the quaternary ammoniumgrouping, the structure of the tertiary amine radical N(tert) can bevaried very widely. Thus, this radical can be either cyclic or acyclicin structure and the groups attached to the nitrogen can be chosen froma great number of hydrocarbon or substituted hydrocarbon radicals. Forpractical reasons, however, I prefer to limit the scope of the radicalN(tert) to those cyclic and acyclic tertiary amine radicals containingnot more than 20 carbon atoms. Moreover, from this restricted group ofradicals, I prefer to exclude aromatic amine radicals which have an arylradical attached directly to the amino nitrogen atom, since the lowbasicity of the arylamines leads to preparative difficulties andresultant lowered yields of products.

The iminoalkyl-(quaternary ammonium) can be represented in a preferredscope by the following structural formulation, wherein N(tert) isrepresented in a more specific fashion as NR R R R R1 air-Livia:

n R3 where R is an aliphaticor aralkyl radical; and R and R when takenseparately, represent monovalent organic radicals other than arylradicals and preferably containing 1-10 carbon atoms each, or R and Rtaken together with the quaternary nitrogen atom form a 5-6 memberedsaturated heterocyclic ring which may additionally contain oxygen orsulfur.

The aliphatic or aralkyl radicals represented by R are, for example,alkyl radicals, alkenyl radicals, and benzyl radicals. The preferredradicals of this type are alkyl and alkenyl radicals containing 1-7carbon atoms, such as methyl, ethyl, n-butyl, n-heptyl, allyl,methallyl, etc. and (monocyclic aryl)methyl radicals containing 7-10carbon atoms, and which may carry inert substituents on the ring such asalkyl, alkoxy, or halogen, e. g. benzyl, 2,4,6-trimethoxybenzyl,p-methoxybenzyl, pchlorobenzyl, methylbenzyl, etc.

The monovalent organic radicals represented by R and R includesaturatedand unsaturated aliphatic and cycloaliphatic radicals, and aralkylradicals. As examples of these monovalent radicals, there are includedalkyl radicals such as methyl, ethyl, n-propyl, ispropyl, u-butyl,isohexyl, etc.; alkenyl radicals such as allyl, methallyl, etc.; aralkylradicals such as benzyl, phenethyl, p-chlorobenzyl, p-methoxyb'enzyl,o-ethoxybenzyl, etc.; cycloalkyl radicals such as cyclohexyl,cyclopentyl, etc.; and cycloalkenyl radicals such as 2-cyclohexenyl,Z-cyclopentenyl, etc. The preferred monovalent radicals are loweraliphatic radicals containing l-7 carbon atoms, such as lower alkyl andlower alkenyl radicals, and lower aralkyl radicals containing 7-10carbon atoms, such as (monocyclic aryl) methyl radicals, e. g. benzyl,halobenzyl, and alkoxybenzyl radicals.

When R and R are taken together with the nitrogen atom to form asaturated.5'6 membered heterocyclic ring, the quaternary ammoniumradical includes cyclic quaternary ammonium radicals as:

(a) Quaternary piperidinium radicals, for example R CH2CH2 CHz-CH:

radical.

R1 CH2CH2 l/ 7N\ /CH2 An err-om Hz (b) Quaternary morpholinium radicals,for example I? CHz-CE:

and

-N A OHzCz (c) Quaternary pyrrolidinium radicals, for example R1 GHQ-0H2A11 CHr-CHz and (d) Quaternary thiamorpholinium radicals, for example R1OHr-CHZ l/ Radicals of the foregoing type wherein one or more carbonatoms of the bridge bear one or more methyl or ethyl groups assubstituents, as represented for example by the 1,2-propylene radical,-CH(CH3)CH2-, also fall within the scope of my invention. The group Ypreferably contains a total of 2-7 carbon atoms.

The preparation of my new quaternary compounds is conveniently carriedout in many instances by direct quaternization of the appropriateN-[(tertiary amino)- alkyl]amino-p-benzoquinones. Thus, for example,pbenzoquinones containing the (tertiary amino)alkylamino grouping-NR-Y--NR R attached to the 2-position, or 2- and S-positions, of thep-benzoquinone nucleus are quaternized by treatment with an alkylatingagent which is an ester of an aliphatic or araliphatic alcohol havingthe formula R -OH with a strong organic or inorganic acid, said esterhaving the formula R An where An is the non-toxic anion of the strongorganic or inorganic acid. A preferred group of these alkylating agents.comprises esters of primary aliphatic and araliphatic alcohols withstrongorganic or inorganic acids. These agents include for example,methyl iodide, methyl bromide, methyl p-toluenesulfonate, dimethyl-sulfate, ethyl iodide, ethyl p-toluenesulfonate, ethyl chloroacetate,n-propyl iodide, a'llyl chloride, allyl bromide, n hexyl bromide, benzylchloride, benzyl bromide, p-methoxybenzyl chloride, pchlorobenzylchloride, etc. The esters of methyl, ethyl,

allyl, and benzyl alcohols are especially useful. The generalquaternization reaction proceeds according to the following equation:

+ R -Am It will be appreciated that when Z repreesnts animinoalkyl-(quaternary ammonium) radical, the original amine employedfor obtaining the above starting material has the formula and the twomoles of the ester, R -An which are required for the completequaternization reaction can be added more conveniently in a single step.The quaternization of the amines is simply and conveniently carried outby mixing the selected amine with one or two molecular equivalents ofthe ester, R An as required, plus an excess of the ester if desired. Thereaction of the ester with the amine can be facilitated by heating thereaction mixture. This is especially advantageous when employing anaraliphatic ester such as benzyl chloride as the quaternizing agent, butmay be unnecessary or undesirable, for example, in the case of alow-boiling lower alkyl ester where the reaction proceeds withsufiicient rapidity at room temperature.

In those instances where the anion, An, is derived from a relativelyweak acid such as citric acid or tartaric acid, the direct addition ofthe ester R An to the tertiary amine does not readily occur due to theproperties of the particular ester employed. In such cases it ispossible by use of metathetical reactions to replace the anion An of onequaternary ammonium salt by a different anion without reconversion tothe tertiary amine. This is usually effected by treatment of an aqueoussolution of the quaternary ammonium salt containing the anion An withsilver oxide (hydroxide). The silver salt Ag-An is precipitated, leavingin solution the quaternary ammonium hydroxide. It is prerequisite, ofcourse, that the salt Ag-An be insoluble in water. The quaternaryammonium hydroxide may then be neutralized with the appropriate acidH--An, which can be either a strong or a lweak organic or inorganicacid, to give any desired sa t.

The new amines of my present invention can be prepared conveniently bythe following procedures. Those amines having one (tertiaryamino)alkylamino group, NHY N=B, are obtained by interacting ap-benzoquinone having the formula where Z is hydrogen, .(loweralkyl)amino, or di(lower alkyl)amino, with one molecular equivalent of aprimary N-[(tertiary amino)alkyll-amine under conditions of mildoxidation, such as obtained by passing air or, preferably, oxygenthrough the reaction mixture during the reaction period, which generallyrequires several hours and is conveniently carried out overnight, i. e.for 6-20 hours, or longer. The reaction proceeds according to thefollowing equation:

When Z is hydrogen, a second (tertiary amino)alkyh amino group can beintroduced readily into the 5-position of the 2-[(tertiaryamino)alkylamino1-p-benzoquinone by causing a second molecularequivalent of the alkylene' diamine, H2N-Y N=B, to react. Thus,

N-Y1N=B l 1 HN-Y -N=B I -1!IY1-N=B 0 t The 2-[ (tertiary amino)alkylamino] -p-benzoquinones also react with primary and secondaryalkylamines under conditions of mild oxidation to introduce a5-alkylamino or S-dialkylamino group, respectively, into thep-benzoquinone nucleus, as illustrated by the following equation:

If it is desired that the (tertiary amino)alkylamino groups introducedat positions 2 and 5 of the p-benzoquinone nucleus as above-described beidentical, the reaction canbe carried out either in one operation byreacting p-benzoquinone with two molecular equivalents of thealkylenediamine or, less conveniently, in two steps, introducing firstone (tertiary amino)alkylamino group and then the other. When, on theother hand, it is desired to introduce different (tertiaryamino)alkylamino groups at positions 2 and 5,, the reaction must ofcourse be carried out in stepwise fashion, causing first onealkylenediamine to react and then the other.

The introduction of a single (tertiary amino)alkylamino group into thep-benzoquinone nucleus can be carried out by employing substantially onemolecular equivalent of the alkylenediamine, H N--Y NR R per equivalentof the p-benzoquinone, or alternatively,

the reaction can be .carried out in. concentratedsolution so that theZ-(tertiary aminoalkylamino)rp-b'enzoquinone precipitates from thereaction medium as it is formed, in which case a considerable excess ofthe alkylenediamine can be employed to increase the speed ofreactionwithout the disadvantage of producing an appreciablequancity ofthe 2,5-bis-(tertiary'am-inoalleylamino)-p-benzoquinone when the biscompound is an undesired byproduct.

Instead of employing p-benzoquinone as such, hydroquinone can beemployed as the starting material, the hydroquinone being converted bythe oxidizing atmos- Pherelfurnished, for example, by use of a mildoxidizing agent such as hydrogen peroxide, oxygen, air, a quinone, etc.)of the reaction mixture to p-benzoquinone. However, when hyd-roquinoneis employed, the reaction time required is increased, and therefore Iprefer to use pbenzoquinone itself.

The use of oxygen in' maintaining the oxidizing atmospherein thereaction mixture. is generally to be preferred over use of air,"sincethereaction: proceedsmore rapidly when oxygenis employed; However,theuse of air ofiers a;useful alternativewhen-Ioxygen is not available.In. the preparation of mono-(tertiary amino)alkylamino-pbenzoquinones,it is convenient to employ an excess of the p-benzoquinone amounting toabout one molecular equivalent or more in the reaction to function as amild oxidizing agent, in which case the use of gaseous oxygen or air isnot necessary. This procedure has the added advantage that the reactiontime required is usually only about one-half to one hour, while whenoxygen or air is used as the oxidizing agent the reaction time isusually at least several hours. The interaction of the p-benzoquinonewith the alkylenediamine is advantageously carried out in a solvent, thechoice of which can be made from a wide variety of organic solvents. Ihave found that dioxane, acetonitrile, and benzene, for example, areexcellent solvents for use in my process and are somewhat moresatisfactory in this regard than are water and alcohol.

- My invention'is illustrated by the following examples without-,ihowever, .being "limited thereto.

. NHr-CHa-CHrCHrNUJzHs)! 104 g. of N,N-diethyl-1,3-propanediamirie was.added to 44 g. benzoquinone in 500 ml? of dioxane, with .provision forexternal-cooling of'the reaction mixture'when necessary. Oxygen wasbubbled through the solution. forapproximately 20 hours. The reactionmixture was then cooled in an ice-bath. A red crystalline precipitateformed and this:.was filtered oif and recrystallized from hot ethanol.There was thus obtained, as a red crystallinec ompound, 35 g. of2,5-bis-(3-diethylaminopropylamino)-p-benzoquinone, which melted at122124 C. A small additional. crop of this product was obtained byconcentration of the dioxane mother liquor.

Analysis.Calculated: N, 15.37%; C, 65.89%; H 9.96%. Found: N, 15.18%; C,65.91%; H, 9.68%.

The compound formed a dihydrochloride which was ogtained as a red powderwhichmelted at 250-251 C. ec.).

B. 2,5-bis-(3-a'iethylamin0propylamino)-pbenzoquinone bis-(benzylchloride) mixture was refluxed for four hours and-was then cooled.-

An equal volume' ofether. was added to the reaction" mixture,- thusprecipitating-a red oil which crystallized-- C. 2,5-bis-(3-diethylaminopropylamina) -pbenzoquinone bis-methobromide-z Asolution'of 5 g. of2,5-bis-(3-diethylaminopropylamino)-p-benzoquinone:in' 100 ml. ofethanol was mixed at'about C. with methyl bromide. After the mixtore-had stood'foraboutZhours, a precipitateformed (in another run, theprecipitate formed after addition of ether-to the reaction mixture). Theprecipitate was collected, washed with dioxane, andfdried'in'an oven at80 C. There" was thus obtained 7.7 g; of 2,5-bis-(3diethylaminopropylamino)-p-benzoquinone bis-methobromide-as an orangepowder which melted at 225 C.

When the quaternization was repeated using a 1:1 mixture ofethanolanddioxane asthe' solvent, the desired bisirdnethobromide'wasobtained in substantially the same we D. Alternatively, the.bis-methobromide described in part C above is prepared by interactingethyl bromide.

with 2,5 -bis-(3-ethylrnethylaminopropylamino) -p-benzowhich is obtainedby interaction of N-ethyl-N-methyl- 1,3-propanediamine andp-benzoquinone in the presence of oxygen by a procedure. similar to thatdescribed in part A above.

EXAMPLE 2 A. 2-(S-dimethylaminopropylamino)-p-benz0quin0neNH-CH2-CH2CH1N(CHa)a I 0 To a solution of 5.4 g. of p-benzoquinone in 50ml. of dioxane there was added 10.2 g. of N,N-dimethyl-l,3

propylenediamine and-the oxygen was bubbled through CHz-CoHs 35f g.-.of'2,5,-b'is-( 3-diethylaminopropylarnino) -p-benzoquinone was dissolvedin 500 ml. of 95 ethanol, and 60 g.'..of. benzylchloride-was added-to.the solution. The

the. solution for four hours.

then concentrated under. reduced pressure and water Analysis:Calculated:N, 1010; Br. 28.82%. Found? The reaction mixture was was added. totheresidue. The solid whichprecipitated.

was collected on a filter and recrystallized from aqueous There wasobtained in this manner 6.8 g. of.

ethanol. 2-(3-dirnethylaminopropylamino)-p-benzoquinone, which melted at159160 C.

Analysis.Calculated: N, 13.44%; C, 63.40%; H, 7.74%. Found: N, 13.29%;C, 63.18%; H, 8.05%.

B. Quaternary salts of 2-(3-dimethylamin0pr0pylamino)-p-benzoquinone2-(3-dimethylaminopropylamino)-p-benzoquinone reacts with benzylchloride and with p-chlorobenzyl chloride to yield, respectively,2-(3-dimethylaminopropylamingB-p-benzoquinone benzyl chloride, which hasthe orm a O CHPCQHI NHCHr-CH2-CHz-NCHI and2-(3-dimethylaminopropylamino)-p-benzoquinone pchlorobenzyl chloride,which has the formula To a solution of 12 g. p-benzoquinone (excessp-benzoquinone employed as oxidizing agent) in 100 ml. of dioxane therewas added 7.5 g. of 1-(3-aminopropyl)p1- peridine and the solution wasstirred for one hour. Thereaction mixture was then cooled and thecrystals which separated from solution were collected on a filter andrecrystallized from hot ethanol-dioxane solution. There was thusobtained 5 g. of 2-[3-(1-ptper1dy1)propy1- aminoJ-p-benzoquinone in theform of red crystals, which melted at ZOO-201 C. (dec.).

Analysis.--Calculated: N, 11.29; C, 67.71%; H, 8.12%. Found: N, 10.97%;C, 67.38%; H, 8.38%;

The compound formed a hydrochloride which was obtained as a light brownpowder which melted at 251- 255 C.

B. Quaternary salts of 2-[3-(I-piperidyDpropylamino]- p-benzoquinoneGlitz-CH2 'Br I which melted at 255 C.

Analysis.-Calculated: N, Found: N, 8.13%; Br, 23.70%.

The aminereacts'with allyl bromide to yield '2'-[3-'(l-"piperidy1)propylamino]-p-benzoquinone allyl bromide,

CH=CHa GEE-CHI, Nit-cuf-cm-cnl-rq on, I CHa-Ca Br I EXAMPLE 4 2 [3 (1pyrrolidynpropylamino] p benzoqainon 5 and quaternary salts thereof CHz-H:

When 7.3 g. of 1-(3-aminopropyl)pyrrolidine is substituted for the 7.5g. of 1-(3-an1inopropyl) piperidine in the procedure described in part Aof Example 3, there is obtained as the product of the reaction2-[3-(l-pyrrolidyl) propylamino]-p-benzoquinone, which has the formula 0CHz-CH:

-. and which reacts with benzyl chloride and with allyl chloride, whichhasthe formula chloride to yield, respectively, 2-[3-(1-pyrrolidyl)propylaminoJ-p-benzoquinone benzyl chloride, which has theformula O GE's-05H;

I CHr-CHI NHCH:GH:CH:N

' A v CHz-CH:

' 1 0 and 2-[3-(pyrrolidyl)propylamino]-p=benzoquinone allyl O CHr-CH -CH:

v GHQ-CH2 NH-GHa-CHz-CHa-N CHz- H:

EXAMPLE 5 A. 2,5 bis (3 dimethylarninopropylamino) p benzoquinoneNH-CHrCHrCH:-N(CH:):

(CHshN-CHz-CHs-CHa-NH B.- Quaterr'uzry' salts of 2,'5-'b'is-(3dimethylaminpropyllizediromhot'petrolumetherr There was thus-obtained'tamino).-p -benzoq.uinone 14L5 of I2,5=bis-('3-di-n-propylaminopropylamino)-p-benz'oqui'n'one in the formof red crystals which melted at- Using a procedure similar to thatdescribed in Ex- 65 66 C, ample 1B,2,5-bis-(3-dimethylaminopropylamino)-p-ben- 5 Analysis-Calculated: N,1'3;34'%. Found: N,

zoquinone washeated with an ethanolic solution of benzyl chloride, thusyielding 2,5-bis-(3-dimethylaminopropyl- B. Quaternary salts of2,5-bis-(3-diz-propylaminopropylamino)-'benzoquinone' ,bis-(benz'ylchloride) as the dil-P-benzoqumone hydrate, 2,5 bis (3 di npropylaminopropylamino) p- GHt -CuHs' NHCH2CHr-CHz-N'CH; .2H2O CoHr-CH:t \cH I CHr-N-CHE-CHr-CHz-NH OH: I

which had an indefinite melting point, ca. 205-225 C.

Analysis calculated: N 938% C1, 1 187% H2O, benzoqumone was quaternlzedby treatment w th two mo lecular equivalents of benzyl chloride to yield2,5-bis- ;ggg 938% H (Karl 3-di-n-propylamino)-p-benzoquinonebis-(benzyl chlo- Two equivalents of methyl iodide react with the aminende) GHQ-05H; NHCH:CH2CHzN (n-CZE7) GuHs-CHP 1 (n-GaHv)(n-CzH1)NCH2-CHa-CH2NH to yield2,5-bis-(3-dimethylaminopropylamino)-p-benzoquinone bisqnethiodide.which had an indefinite melting point.

40 NH-CHfl-C Hi-CHrN-CH: CH3

0-H; CH7N-CHz-CHa-CHrNH OH EXAMPLE 6 A. 2,5 b'is (3di-n-propylaminopropylamiho) pbenzaquinone The amine reacted with twomolecular equivalents of NH-C'Hr-CH-CH-NQ-Calii):

of d oiaii e t li i e ai ad de 2 T;. 7 gF I I?I di ngp ;1 .methyl'itiromidet to fi 1,3-propanediamine, and oxygen was bubbled through thePropylammo) ip'benz'oqumone bls'methobmmlde 0 H /CH:

NH-CHzCH:'CHF-N-'(n-OaH1)' CH: n-cmn-N-crn-om-cHr-NH Br solution forforty hours. The reaction mixture was conwhich melted at 2O2-'-204C.centrated under reduced pressure and the residue was The amine reactswith two molecular equivalents of diluted with water; Anaoilwhichlatersolidified separated allyl chloride to yield2,5-bis-(3-di-n-propylaminoprofrom the aqueous layer. This solid productwas crystal- .pylamino) -p-benzoquinone bis-(allyl chloride),

1 (11-CaH7) 13 14 EXAMPLE 7 A. 2,5 bis [3 (1 piperidyl)propylamin] pbenzoquinone GE's-CE! NH-CHr-CHr-C'Ha- CH: CHr-OHI CHa-C CH2N-CHz-CHz-CHrNH CHr-C a To 3.6 g. of2-[3-(1-piperidyl)propylamino]-p-benzowas repeated, using substantiallyone equivalent of the quinone in 150 ml. of hot dioxane there was added4 g. 15 alkylenediamine instead of an excess, the yield of 2-(4- of1-(3-aminopropyl)piperidine, and oxygen was passeddiethylaminobutylamino)-p-benzoquinone obtained was into thehotthsolution dfor twenty hokillrsl.1 The reaction only slightly lessthan that obtained in A.(1).

mixture was en coole The solidw ic separate from solution was collectedon a filter and recrystallized from Quaternary g iggz' fg hot ethanol.There was thus obtained 3 g. of 2,5-bis- [3 (1 piperidyl)propylamino] pbenzoquinone in 2-(4-diethylaminobutylamino) p benzoquinone was the formof orange-red crystals which melted at quaternized by treatment withone, molecular equivalent 179-181 C. of methyl bromide to yield2-(4-diethylaminobutyl- Analysis.-Calculated: N, 14.42%; C, 68.00%; H,amino)-p-benzoquinone methobromide, 9.34%. Found: N, 14.26%; C, 68.24%;H, 9.59%. 0

CH: B. Quaternary salts of 2,5-bis-[3-(I-piperidyl)prapylamino]-p-benz0quin0ne Br C1112,5-bis-[3-(1-piperidyl)propylamino]-pbenzoquinone was quaternized bytreatment with methyl bromide to yield 2,5bis-[3-(1-piperidyl)propylamino]-p-benzoqui- 0 none bis-methobromide,which melted at 146148 C.

CH: CHrOH: NH-CHaCH2CH2-N CH:

CHa-CH: CH:

Br CHr-C r Cg: N C Hz-CHa-CHrNH CHr-CH: l 6

The amine reacts with benzyl chloride to yield 2-(4- which melted at253C. (deg). giighylaminobutylamino)-p-benzoquinone benzyl chlo-Analysis.Calculated: N, 9.68%; Br, 27.60%. Found: 7 0 N 963% Br 27 vCRT-011 NHCEr-CHrCHr-CH2NC2H5 The amine reacts with two molecularequivalents of 01 CH 2 5 benzyl chloride to yield2,5-bis-[3-(l-piperidyl)propylamino]-p-benzoquinone bis-(benzylchloride),

o CHrCuH O H CH CHz-CH: 7 NH-OHz-CHr-CHz-N cni cnz-ont l 1 CHr-C 1 CH2 NCH2CHrCH2-NH OHr-C a C1 EXAMPLE 8 EXAMPLE 9 A.2-(4-diethylaminobutylamino)-p-benzoquin0ne A.2-(4-diethylaminobutylamino-S-methylamina- 0 p-benzoquinane oNHCH2CH2CH2CH2-'N(C2H5)I I NH-CH2CH2-CH2CHr- 2 i) onrNn (1) To 8.7 g. ofp-benzoquinone in 100 ml. of dioxane 0 there was added 23 g. (oneequivalent plus an excess) of N,N-diethyl-1,4-butanediamine and oxygenwas passed 3 g. of 2-(4-diethylaminobutylamino)-p-benzoquinone into thereaction mixture for about twenty hours. There was dissolved in 100 ml.of dioxane, and methylamine was obtained a crystalline precipitate whichwas coland oxygen were bubbled simultaneously into the solulected on afilter. The mother liquors were concentrated tion'for two hours. Thesolution was concentrated under to yield a second crop of the product.The combined reduced pressure and the residue was dissolved in bencropsof product were recrystallized from an ethanolzene. The benzene solutionwas dried over sodium sulwater mixture. There was obtained in thismanner 8.8 fate, filtered, and petroleum ether was added to the solug.of 2- (4- diethylaminobutylamino)-p-benzoquinone, tion, therebyprecipitating l g. of 2-(4-diethylaminobuwhich melted at l23l25 C.tylamino)-5-methylamino-p-benzoquinone, a yellow solidAnalysis.Calculated: N, 11.19%; C, 67.16; H, 8.86. which melted at103-106 C.

Found: N, 11.23%; C, 67,24; H, 9.08. Analysis.-Calculated: C, 64.48%; H,9.02%. Found:

(2) When the preparation described in A (1) above C, 64.28%; H, 9.04%.

1 5! 16 B. Quaternary salts of 2-(4-diethylaminobatylamino)-5-amino-p-benzoquinone allyl bromide, which has theformethylamino-p-benzoqainone mula 2(4-diethylaminobutylarnino)-5-methylamino-p-ben- 1 CHr'CE=CH zoqumonereacts with benzyl chloride and with methyl H H 0H 3H oH,-N-02H6 sulfateto yield, respectively,2-(4-diethylaminobutylamino)-5-methylamino-p-benzoquinone benzylchloride, (OHQEN Br which has the formula II 0 and 2(4-d1ethylam1nobutylarn1no)5-d1methylam1no-p- CHPWH benzoquinone methylp-toluenesulfonate, which has the NH-0H=- -0H2cHr-cH=N-czm formula 0 HCHr-NH l I -NH-OH2GHrCH2CHzNC2Hs i) CzHt (CHs)2N- aS-Ca r i-(P)) and 2-(4- diethylaminobutylamino)-5-methylamino-p- 0 EXAMPLE 11 A.2,5-b'is-(4-diethylaminobutylamino) p-benzoqainone 0 II I lNH--CH2CHzCH2CHz-N(CzH )z (C2Hs)2N-CHzCHz-CHzCHr-NH benzoquinonemethosulfate, which has the formula To 8.3 g of 2 (4diethylaminobutylamino) p benzo CH3 quinone in 100 m1. of dioxane therewas added 6.3 g. v 7 (a 50% excess) of N,N-diethyl-1,4-butanediamine,and NH-CHz-CHz-OHrCHrbFCzH oxygen was passed into the mixture whilekeeping the C211, temperature of the mixture at 3540 C. for about thirtyso CH 40 hours. The solution was then concentrated and the 4 a) residuethus obtained was recrystallized from hot petro- 0 leum ether. There wasobtained 4.5 g. of 2,5-bis-(4- EXAMPLE 10diethylaminobutylamino)-p-benzoquinone, which melted t 10516 C.Z-(4-dzethylaminobatylamino)-5-dzmethylamin0-pa benzoqu'none andquaternary salts thereof gf g fifig fgQ g: 23

l B. Quaternary salts of 2,5-bis-(4-diethylamin0batyl-NHCHzCH2CH2CHr-N(C2Hs)2 amino)-p-benzoqu'inon'g (CHa)2N 2,5 bis(4-diethylaminobutylamino)-p-benzoquinone I was quaternized with twoequivalents of methyl bromide 0 to yield2,5-bis-(4-diethylaminobutylamino)-p-benzoqui- By substitutingdimethylamine for the methylamine none iils'methobromlde' 5 which meltedat 229230 C. employed in Example 9A, there is obtained as the prodgggi'gf gt g a i' 956% Found net of the reaction2-(4-diethy1aminobutylamino)-5-di- The amine reacted with two molecularequivalents of benzyl chloride to yield2,5-bis-(4-diethylaminobutylamino)-p-benzoquinone bis-(benzyl chloride),having the structural formula methylamino-p-benzoquinone, which reactswith allyl l CHz-CtH NH--OHz'CHz-CHz-OHzN-CzH CaHs-CHB .7 1 02115CzHr-N-CHr-G Hr -C Hz-CHz-NH p p which was a red, amorphous compoundhaving an indebromide and with methyl p tolu'enesulfonate to yield,finite melting point.

Similarly, the amine reacts with ethyl chloride to yield respectively,2- (4-diethylaminobutylarnino)-5-dimethyl-2,5-bis-(4-diethylaminobutylamino)-p-benzoquinone bisethochloride.having the structural formula CaHs CaHs-N-CHa-CHa-CHz-CHr-NH 24 g..ofN,N-diethy l-1,5:pentanediamine was added amino,amylaminofl p-benzoquinone bis (methyl-f' p toluwitlrcooling;v to g; ofpgbenzoquinone. in" 15.0 ml. of encsulfonate)=,;

EXAMPLE A; 2;.i.-bis-.[$.-(1piperidy l-)amylamino]rprbenzoqainonez "fCHa-CH:

NH-CHr-(CH2)3CH2N: CH2 0112-011, g Q (3112-0 1 C 1 NCH:--( QH2)3-CHr-'NHCH2--C 2 dioxane. Oxygen was passed into the slightly warm solug. of1-(5-arninoamyl)piperidine was. added with tion for twenty hours. Thereaction mixture was then. cooling ,to a solution of 15. g. (anexcess)of p-benzoonce tra ed n en reducedpressure Y to a; thick. Slush quinonein-..30(m11of-:dioxane; The solutiomwaswarmed which was filteredzTheacollectedr solid-was,- dissolved and" oxygen was bubbled; int'othe";warm solution: for in ethanol andwateawasaddecl to-tthealcoholic..solutwenty hours. The reaction-mi-xture was" concentratedtion, thereby causing the.- separation of a-.-dar k.rred. oi underreduced pressure: The concentrated solution was which crystallizedonstanding, The; crystalline solid cooled andthe red crysfalline solidwhich separated which weighedit4 9- g;., was 2,5-bis-(fifdiethylaminoamylwas collected on a filter. This solid' wasrecrystallized aminoyp-benzoquinone, Itmeltedat: 92:95? C. from 95%ethanol to yield 9 g. of 2,5-bisl-[5-(1-piper- 2%2gysis- C 1Qu-1a1ejd:N,-., 13n32f7bt Eounzd: N, idyl)amylaminoJPp-benzoquinone.

1' a at B. Quaternary salts of 2,5-bis-(5-a'iethylamih0amyl' B.Quaternarymalis of"2ls bis ['5 (l piperid)il)amylaminoy-p-benzoquinone;y aminol-p-benzoquinone 2 g. of2,5-bis-(S-diethylaminoamylamino)-p-benzoquinone was quaternized bytreatment with methyl 2,5-bis-[5-(1-piperidyl)amylamino] p benzoquinonebromide in ethanolic solution, andether was then added reacts with twoequivalents of methyl bromide, to yield to the reaction mixture: The redoil which precipitated: 2,5-bis-[5-(l-piperidylz)amylaminod-p-benzoquinone bissolidified on standing to yield 2.5 g. of2,5-bis-(5-diethylmethobromide fi H Tl CzHs CHE-CE:

; nna-omeonmeah 1- on,

GET-CH2 02H I CHE-C z C\?.-. N-CH2(CH2):-CH2NH- (so 0 H) CHi -CaS04C2H5) 0 4 a aminoamylamino) '-p-- benzoquinone bis-methobromide,which meltedat. 264 -2 f C... having the formula 7 I /C;Hit mi-onrom-cm-N-wamp CH:

I'C'CIHIQ C2Hs-N-CH2-(CHDPCHrNH C2115 a 0 v r I I which melted atl12-l13 C. Analysis.Calculated:-. N,, 8.83%; .Br,, 25.19%.

Analysis.'-Calculated:: -N, 9.18%; Br; 26.19%. Found: N; 8.90%; Br,"25.25%. Found: N, 9.07%; Br, 25.68%. The amine reactswi'th'diethyl"sulfate to yield 2,5-bis- The aminereacts;witl1'=:twomolecularequivalentsof[5.-(-l-piperidyl)amylamino=lpbenzoquinonea bis-:(ethomethylp-toluenesulfonate to yield:2,5-bis*(5:diethylsulfate. .5

.. CH: Clix-CE: 'NH-cHrorm-cm-N CH2 CHfl-CH: CH; t g Bl CHz-C 2 CH2 NOH2(CH2)a-CH:-NH

OHa-Cfia Br EXAMPLE 14 methyl bromide, there 'was obtained 2-lY5-(1-piper- A. 2-(S-diethylaminoamylamino) p-benzoquinone ldyl)amylammo] ip'benzoqmmm gz q I II GHz-CHt NH-CE-(CHQr-CHT-N (@2119: 15NH-CHr-(CHah-CHr-N on,

Clix-O6:

I Br 0 0 Employing a procedure similar to that described in part A ofExample 2, one equivalent of N,N-diethyl-l,5-

pentanediamine was reacted with p-benzoquinone under conditions of mildoxidation. There was thus obtained 2-(S-diethylaminoamylamino) pbenzoquinone, which melted at 84-86 C.

Analysis.Calculated: N, 10.60%. F ound: N, 11.19%.

B. Quaternary salts of 2-(S-diethylaminoamylamino)- p-benzoqainone 2-(5diethylaminoamylamino) p benzoquinone was quaternized by treatment withone equivalent of methyl bromide to yield2-(S-diethylaminoamylamino)p-benzoquinone methobromide, I

NH-CHr-(CH2)i-CH:N

02H! Br 0 which had an indefinite melting point, ca. 113 C.

Analysis. Calculated: N, 7.79%; Br, 22.22%. Found: N, 7.57%; Br. 22.92%.

The amine reacts with one equivalent of benzyl chloride to yield2-(S-diethylaminoamylamino)-p-benzoquinone benzyl chloride,

Using a procedure similar to that described in part A of Example 3,p-benzoquinone was reacted with one equivalent ofl-(5-aminoamyl)piperidine. After concentrating the reaction mixture,there was obtained as a product 2- [5-( l-piperidyl) amylamino]p-benzoquinone, which melted at 176177 C.

Analysis.Calculated: N, 10.14%; C, 69.53%; H, 8.75%. Found: N, 9.98%; C,69.63%; H. 8.97%.

This amine reacts with hydrobromic acid to yield the amine hydrobromide.

' B. Quaternary salts of 2-[5-(1 piperidyl) amylaminolp-benzoquinon'eWhen 2-[5-(l-piperidyl)amylamino]-p:benzoquinone was quaternized bytreatment with one equivalent of The amine reacts with allyl bromide toyield 2-[5-(1- piperidyl)amylamino]p-benzoquinone allyl bromide 1. Amember of the class consisting of 2-[(tertiary amino)alkylamino]p-benzoquinones having the formula NH--Y'N=B where N=B is atertiary amino radical selected from the group consisting of di-(loweralkyl)amino radicals, l-piperidyl radicals, and l-pyrrolidyl radicals, Yis a lower alkylene bridge interposing 3-5 carbon atoms between the twonitrogen atoms connected by the bridge, and Z is a member of the groupconsisting of hydrogen, (lower alkyl)amino radicals, di-(lower alkyl)amino radicals, and- (tertiary amino)alkylamino radicals having theformula NH-Y'N=B; and acid addition salts thereof.

2. A member of the class consisting of 2-[(tertiaryamino)alkylamino]p-benzoquinones having the formula where N=B is a di-(lower alkyl)amino radical and Y is a lower alkylene bridge interposing3-5 carbon atoms between the two nitrogen atoms connected by the bridge;and acid addition salts thereof.

. 3. A member of the class consisting of 2-[(tertiaryamino)alkylamino]p-benzoquinones having the formula Where N=B is al-piperidyl radical, and Y is a lower alkylene bridge interposing 3-5carbon atoms between the two nitrogen atoms connected by the bridge; andacid addition salts thereof.

21 4. A member of the class consisting of 2,5-bis-[(tertiary amino)alkylamino] -p-benzoquinones having the formula where N=B is al-piperidyl radical; Y is a lower alkylene bridge interposing 3-5 carbonatoms between the two nitrogen atoms connected by the bridge; and acidaddition salts thereof.

6. A member of the class consisting of2,5-bis-(3-diethylaminopropylamino) p benzoquinone, having thestructural formula NH-CHr-CHz-CHa-NKhHa):

(C2115) zN-OHr-CHa-CHz-NH and acid addition salts thereof.

7. A member of the class consisting of2,5-bis-(3-dimethylaminopropylamino)-p-benzoquinone, having thestructural formula -OHrOHa-OHa-N(OH:):

(OHahN-OHz-CHrOHs-NH and acid addition salts thereof.

8. A member of the class consisting of2,5-bis-(5-diethylaminoamylamino)-p-benzoquinone, having the structuralformula 9. The process for preparing a 2-[(tertiary amino)-alkylaminol-p-benzoquinone having the formula where Y is a loweralkylene bridge interposing 3-5 carbon atoms between the two nitrogenatoms connected by the bridge, and N=B is a tertiary amino radicalselected from the group consisting of di-(lower alkyl)amino, lpiperidyl,and l-pyrrolidyl radicals, which comprises reacting p-benzoquinone withone molecular equivalent of an amine having the formula H2N-Y N=B underconditions of mild oxidation.

10. The process for preparing a 2-[(tertiary amino)- alkylamino]-5-Z-p-benzoquinone having the formula where Y is a lower alkylene bridgeinterposing 3-5 car bon atoms between the two nitrogen atoms connectedby the bridge, and N=B is a tertiary amino radical selected from thegroup consisting of di-(lower alkyl)amino, 1- piperidyl, andl-pyrrolidyl radicals, and Z is a member of the class consisting of(lower alkyl)amino, di-(lower alkyl)amino, and (tertiaryamino)alkylamino radicals having the formula NHY N=B, which comprisesreacting a 2-[(tertiary amino)alkylaminol-p-benzoquinone having theformula under conditions of mild oxidation with one molecular equivalentof an amine selected from the class consisting of (lower alkyl)amineshaving the formula (lower alkyl)- NHz, di-(lower alkyDamines having theformula (lower alkyl)2NH, and (tertiary amino)alkylamines having theformula H2N--Y -N=B.

and acid addition salts thereof.

References Cited in the file of this patent P. B. 981, pp. 33-35(19515). Karrer, Organic Chemistry, second ed., pp. 562-3

1. A MEMBER OF THE CLASS CONSISTING OF 2-(TERTIARY AMINO)ALKYLAMINO)-P-BENZOQUINONES HAVING THE FORMULA
 10. THE PROCESS FORPREPARING A 2-((TERTIARY AMINO)ALKYLAMINO)-5-Z2-P-BENZOQUINONE HAVINGTHE FORMULA